The Molecular Genetics Section (MGS) seeks to elucidate the complex molecular/genetic program governing tumor genesis and progression through the development of genetically engineered mouse models of human cancer. A major goal is to identify candidate targets or pathways for both mechanistic enlightenment and future therapeutic utility. Our efforts in this regard are focused on two tumor types, cutaneous malignant melanoma (CMM) and the pediatric malignancy rhabdomyosarcoma (RMS).Exposure to UV radiation is a causal agent in the vast majority of CMM. Retrospective epidemiological data suggest that CMM is provoked by intense intermittent exposure to UV, particularly during childhood. We tested this hypothesis in mice in which expression of a transgene encoding the c-Met ligand, hepatocyte growth factor/scatter factor (HGF/SF), induced sporadic melanocytic tumors in aged animals. We discovered that a single neonatal dose of erythemal UV radiation was necessary and sufficient to induce cutaneous melanoma reminiscent of human CMM with high penetrance and relatively short latency (Noonan et al., Nature 413: 271-2, 2001). A critical role for the INK4a/ARF locus, widely regarded as a key melanoma suppressor in human patients, in our HGF/SF transgenic mouse model was confirmed by demonstrating that UV-induced melanoma was significantly accelerated on a genetic background deficient in Ink4a/Arf (Recio et al., Cancer Res. 62: 6724-30, 2002). These results strongly suggest that sunburn is a significant risk factor in kindreds harboring germline mutations in INK4a/ARF (Merlino and Noonan, Trends Mol. Med. 9: 102-8, 2003). There as been much controversy surrounding the relative risks associated with UVB versus UVA radiation. Recently, we used this HGF/SF transgenic mouse to show that UVB alone, but not UVA alone, is able to induce the full melanoma phenotype (DeFabo et al., Cancer Res. 64: 6372-6, 2004).The childhood malignancy RMS, accounting for 5 to 10% of all pediatric neoplasms and for more than 50% of pediatric soft tissue sarcomas, is thought to arise from imbalances in skeletal muscle cell proliferation and differentiation. However, molecular pathways associated with RMS remain largely unknown, due in part to the lack of an RMS-prone mouse model. In the course of studying genetic interactions between c-MET and the INK4a/ARF locus, we discovered that virtually all HGF/SF transgenic, Ink4a/Arf-deficient mutant mice rapidly succumbed to highly invasive RMS (Sharp et al., Nature Med. 8: 1276-80, 2002). Comparable molecular lesions in c-MET, pRB and p53 pathways have been individually described for human RMS. These data provide genetic evidence that c-MET and INK4a/ARF pathways represent critical and synergistic targets in RMS pathogenesis, and suggest a rational therapeutic combination to combat this pediatric cancer.Patients presenting with metastatic RMS continue to have a very poor clinical prognosis due in large part to our rudimentary knowledge of molecular events that dictate metastatic potential. We have generated numerous highly and poorly metastatic cell lines from the RMS tumors arising in our HGF/SF-transgenic, Ink4a/Arf-deficient mice, which are proving to be a valuable research tool for studying mechanisms associated with metastatic dissemination. cDNA microarray analysis of these cell lines identified a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies revealed that the actin filament-plasma membrane crosslinker Ezrin and the homeodomain-containing transcription factor Six1 had essential roles in determining the metastatic fate of RMS cells. Notably, EZRIN and SIX1 expression levels were also enhanced in human RMS tissue, significantly correlating with clinical stage. The identification of EZRIN and SIX1 as critical regulators of metastasis in RMS provides new mechanistic and perhaps therapeutic insight into this pediatric cancer.